There have been several major accomplishments within the past fiscal year. First, cholinergic modulation of hippocampal synaptic plasticity has been studied extensively by applying receptor agonists or blockers;however, the effect of rapid physiological cholinergic stimuli on plasticity is largely unknown. Here, we report that septal cholinergic input, activated either by electrical stimulation or via an optogenetic approach, induced different types of hippocampal Schaffer collateral (SC) to CA1 synaptic plasticity, depending on the timing of cholinergic input relative to the SC input. When the cholinergic input was activated 100 or 10 ms prior to SC stimulation, it resulted in 7 nAChR-dependent long-term potentiation (LTP) or short-term depression, respectively. When the cholinergic stimulation was delayed until 10 ms after the SC stimulation, a muscarinic AChR-dependent LTP was induced. Moreover, these various forms of plasticity were disrupted by A exposure. These results have revealed the remarkable temporal precision of cholinergic functions, providing a novel mechanism for information processing in cholinergic-dependent higher cognitive functions. Second, the 7 nicotinic acetylcholine receptors (nAChRs) play an important role in cellular events such as neurotransmitter release, second messenger cascades, cell survival and apoptosis. In addition, they are a therapeutic target for the treatment of neurological disorders such as Alzheimer's disease and schizophrenia, and drugs that potentiate 7 nAChRs through the regulation of desensitization are currently being developed. Recently, these channels were found to be localized into lipid rafts. Here we show that the disruption of lipid rafts in rat primary hippocampal neurons, through cholesterol-scavenging drugs (methyl--cyclodextrin) and the enzymatic breakdown of sphingomyelin (sphingomyelinase), results in significant changes in the desensitization kinetics of native and expressed 7 nAChRs. These effects can be prevented by cotreatment with cholesterol and sphingomyelin, and can be mimicked by treatment with cholesterol and sphingomyelin synthesis inhibitors (mevastatin and myriocin, respectively), suggesting that the effects on desensitization kinetics are indeed due to changes in the levels of cholesterol and sphingomyelin in the plasma membrane. These data provide new insights into themechanism of desensitization of 7 nAChRs by providing evidence that the lipid composition of the plasma membrane can modulate the activity of the 7 nAChRs. Third, the nAChRs are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer's disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of amyloid (A(1-42)) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for 42 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the 22 nAChR subtype was not known. The action of dFBr was tested on 22 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the 22 receptor. Next we tested whether dFBr had any effect on the previously known block of both the 42 and 22 receptors by A(1-42). We found that the functional blockade of ACh-induced currents in oocytes expressing 42 and 22 receptors by A(1-42) was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both 42 and 22 subtypes of nAChRs and that it also relieves the blockade of these receptors by A(1-42). This study demonstrates that PAMs for the non-7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders.